Erken Sosyal İzolasyon Sıçanlarda Anksiyete ve Depresyon Benzeri Davranışlar ve Nöroinflamatuar Cevaplara Neden Olur

Öz

Erken gelişim evrelerinde strese maruz kalmak beyin gelişimini olumsuz etkiler ve depresyon ve anksiyete gibi psikiyatrik durumlarla ilişkilidir. Bu çalışmada, 6 hafta kronik sosyal izolasyona tabi tutulan genç erkek Wistar sıçanlarının davranışsal değişiklikleri ve prefrontal korteksindeki (PFC) oksidatif stresi ve inflamatuar mediatörlerin seviyelerini araştırdık. On sekiz erkek Wistar Albino sıçan kontrol ve sosyal izolasyon gruplarına ayrıldı. İzolasyon grubunda yer alan sıçanlar altı hafta boyunca ayrı ayrı barındırıldı. Anksiyete ve depresyon benzeri davranışlar sırasıyla açık alan testi (OFT) ve zorunlu yüzme testi (FST) ile değerlendirildi. Prefrontal kortekste Toll benzeri reseptör 4 (TLR4), nükleer faktör kappa B (NF-κB), glikojen sentaz kinaz 3 beta (GSK-3β), beyin kaynaklı nörotrofik faktör (BDNF), malondialdehit (MDA) ve indirgenmiş glutatyon (GSH) seviyeleri ölçüldü. Grup farklılıkları Mann-Whitney U testi kullanılarak analiz edildi. Sosyal izolasyon grubunda, OFT sırasında merkez bölgede geçirilen süre azalırken, çevre bölgede geçirilen süre kontrollere kıyasla önemli ölçüde arttı ve bu da anksiyete benzeri davranışların arttığını gösterdi. Sosyal olarak izole edilen sıçanlar ayrıca FST'de depresyon benzeri davranışları yansıtan daha fazla hareketsizlik sergilediler ve TLR4, NF-κB, GSK-3β ve MDA seviyeleri yükseldi. Gruplar arasında BDNF ve GSH seviyelerinde istatistiksel olarak anlamlı bir fark gözlenmedi. Yaşamın erken dönemlerinde yaşanan sosyal izolasyon stresinin neden olduğu davranış bozuklukları, PFC'de artan oksidatif stresi ve NF-κB/TLR4/GSK-3β sinyal yolunun aktivasyonunu içerebilir.

Anahtar Kelimeler

• Sosyal izolasyon
• Prefrontal korteks
• Depresyon
• Anksiyete
• İnflamasyon

Early Social Isolation Induces Anxiety- and Depression-Like Behaviors and Neuroinflammatory Responses in Rats

Öz

Exposure to stress during early developmental stages adversely affects brain development and is associated with psychiatric conditions such as depression and anxiety. In this study, we investigated behavioral changes and levels of oxidative stress and inflammatory mediators in the prefrontal cortex (PFC) of young male Wistar rats subjected to 6 weeks of chronic social isolation. Eighteen male Wistar Albino rats were divided into control and social isolation groups. The isolation group was housed individually for six weeks. Depressive- and anxiety-like behaviors were evaluated by the open field test (OFT) and forced swimming test (FST), respectively. Toll like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), glycogen synthase kinase 3 beta (GSK-3β), brain derived neurotrophic factor (BDNF), malondialdehyde (MDA), and reduced glutathione (GSH) levels in the prefrontal cortex were measured. Group differences were analyzed using the Mann–Whitney U test. In the social isolation group, time spent in the center zone during the OFT was reduced, while time in the periphery was significantly increased compared to controls, indicating elevated anxiety-like behavior. Socially isolated rats also exhibited greater immobility in the FST, reflecting depression-like behavior, and showed elevated levels of TLR4, NF-κB, GSK-3β, and MDA. No statistically significant differences were observed between the groups in BDNF and GSH levels. Behavioral disturbances induced by early-life social isolation stress may involve increased oxidative stress in the PFC and activation of the NF-κB/TLR4/GSK-3β signaling pathway.

Anahtar Kelimeler

• Social isolation
• Prefrontal cortex
• Depression
• Anxiety
• Inflammation

Kaynakça

1. Abu-Elfotuh, K., Al-Najjar, A. H., Mohammed, A. A., Aboutaleb, A. S., & Badawi, G. A. (2022). Fluoxetine ameliorates Alzheimer's disease progression and prevents the exacerbation of cardiovascular dysfunction of socially isolated depressed rats through activation of Nrf2/HO-1 and hindering TLR4/NLRP3 inflammasome signaling pathway. International Immunopharmacology, 104, 108488. https://doi.org/10.1016/j.intimp.2021.108488
2. Abu-Elfotuh, K., Darwish, A., Elsanhory, H. M. A., Alharthi, H. H., Hamdan, A. M. E., Hamdan, A. M., Masoud, R. A. E., Abd El-Rhman, R. H., & Reda, E. (2023). In silico and in vivo analysis of the relationship between ADHD and social isolation in pups rat model: Implication of redox mechanisms, and the neuroprotective impact of Punicalagin. Life Sciences, 335, 122252. https://doi.org/10.1016/j.lfs.2023.122252
3. Aswar, U., Shende, H., & Aswar, M. (2022). Buspirone, a 5-HT1A agonist attenuates social isolation-induced behavior deficits in rats: a comparative study with fluoxetine. Behavioural Pharmacology, 33(5), 309–321. https://doi.org/10.1097/FBP.0000000000000679
4. Aykaç, G., Uysal, M., Yalçin, A. S., Koçak-Toker, N., Sivas, A., & Oz, H. (1985). The effect of chronic ethanol ingestion on hepatic lipid peroxide, glutathione, glutathione peroxidase and glutathione transferase in rats. Toxicology, 36(1), 71–76. https://doi.org/10.1016/0300-483x(85)90008-3
5. Casini, A. F., Ferrali, M., Pompella, A., Maellaro, E., & Comporti, M. (1986). Lipid peroxidation and cellular damage in extrahepatic tissues of bromobenzene-intoxicated mice. The American Journal of Pathology, 123(3), 520–531.
6. Chen, T., Liu, S., Zheng, M., Li, Y., & He, L. (2021). The effect of geniposide on chronic unpredictable mild stress-induced depressive mice through BTK/TLR4/NF-κB and BDNF/TrkB signaling pathways. Phytotherapy Research : PTR, 35(2), 932–945. https://doi.org/10.1002/ptr.6846
7. Chmelova, M., Balagova, L., Marko, M., Vrankova, S., Cebova, M., Jezova, D., Riecansky, I., & Hlavacova, N. (2019). Behavioral alterations induced by post-weaning isolation rearing of rats are accompanied by reduced VGF/BDNF/TrkB signaling in the hippocampus. Neurochemistry International, 129, 104473. https://doi.org/10.1016/j.neuint.2019.104473
8. Colucci-D’Amato, L., Speranza, L., & Volpicelli, F. (2020). Neurotrophic factor BDNF, physiological functions and therapeutic potential in depression, neurodegeneration and brain cancer. International Journal of Molecular Sciences, 21(20), 7777. https://doi.org/10.3390/ijms21207777

9. Dandekar, M. P., Valvassori, S. S., Dal-Pont, G. C., & Quevedo, J. (2018). Glycogen synthase kinase-3β as a putative therapeutic target for bipolar disorder. Current Drug Metabolism, 19(8), 663–673. https://doi.org/10.2174/1389200219666171227203737
10. Dávila-Hernández, A., González-González, R., Guzmán-Velázquez, S., Hernández Hernández, O. T., Zamudio, S. R., & Martínez-Mota, L. (2021). Antidepressant-like effects of acupuncture via modulation of corticosterone, sex hormones, and hippocampal BDNF expression in male rats. Brain Research Bulletin, 173, 53–65. https://doi.org/10.1016/j.brainresbull.2021.05.007
11. Dimonte, S., Sikora, V., Bove, M., Morgese, M. G., Tucci, P., Schiavone, S., & Trabace, L. (2023). Social isolation from early life induces anxiety-like behaviors in adult rats: Relation to neuroendocrine and neurochemical dysfunctions. Biomedecine & Pharmacotherapy, 158, 114181. https://doi.org/10.1016/j.biopha.2022.114181
12. Dionisie, V., Filip, G. A., Manea, M. C., Manea, M., & Riga, S. (2021). The anti-inflammatory role of SSRI and SNRI in the treatment of depression: a review of human and rodent research studies. Inflammopharmacology, 29(1), 75–90. https://doi.org/10.1007/s10787-020-00777-5
13. Du, Y., Yan, T., Wu, B., He, B., & Jia, Y. (2024). Research on the mechanism of antidepressive effect of Suanzaoren Decoction through TLR4/MyD88/NF-κB pathway and Wnt/β-catenin pathway. Journal of Ethnopharmacology, 319(Pt 1), 117190. https://doi.org/10.1016/j.jep.2023.117190
14. Dulabi, A. N., Shakerin, Z., Mehranfard, N., & Ghasemi, M. (2020). Vitamin C protects against chronic social isolation stress-induced weight gain and depressive-like behavior in adult male rats. Endocrine Regulations, 54(4), 266–274. https://doi.org/10.2478/enr-2020-
15. Erdem, S., Özaçmak, H. S., Turan, İ., & Ergenç, M. (2024). The protective effect of angiotensin II type I receptor blocker (valsartan) on behavioral impairment, NLRP3, BDNF, and oxidative stress in the brain tissue of ovariectomized female rats. Physiological Reports, 12(20), e70003. https://doi.org/10.14814/phy2.70003
16. Gárate, I., García-Bueno, B., Madrigal, J. L., Bravo, L., Berrocoso, E., Caso, J. R., Micó, J. A., & Leza, J. C. (2011). Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression. Journal of Neuroinflammation, 8, 151. https://doi.org/10.1186/1742-2094-8-151
17. García Bueno, B., Caso, J. R., Madrigal, J. L., & Leza, J. C. (2016). Innate immune receptor Toll-like receptor 4 signalling in neuropsychiatric diseases. Neuroscience and Biobehavioral Reviews, 64, 134–147. https://doi.org/10.1016/j.neubiorev.2016.02.013
18. Gholami-Zanjanbar, M., Soleimanian, F., Reyhani, N., Hajizamani, S., Sajadi, A. E., Ghofrani-Jahromi, Z., & Vaseghi, S. (2024). Synaptophysin and GSK-3beta activity in the prefrontal cortex may underlie the effects of REM sleep deprivation and lithium on behavioral functions and memory performance in male rats. Pharmacology, Biochemistry, and Behavior, 245, 173894. https://doi.org/10.1016/j.pbb.2024.173894
19. Giustarini, D., Colombo, G., Garavaglia, M. L., Astori, E., Portinaro, N. M., Reggiani, F., Badalamenti, S., Aloisi, A. M., Santucci, A., Rossi, R., Milzani, A., & Dalle-Donne, I. (2017). Assessment of glutathione/glutathione disulphide ratio and S-glutathionylated proteins in human blood, solid tissues, and cultured cells. Free radical Biology & Medicine, 112, 360–375. https://doi.org/10.1016/j.freeradbiomed.2017.08.008
20. Gong, W. G., Wang, Y. J., Zhou, H., Li, X. L., Bai, F., Ren, Q. G., & Zhang, Z. J. (2017). Citalopram ameliorates synaptic plasticity deficits in different cognition-associated brain regions induced by social isolation in middle-aged rats. Molecular Neurobiology, 54(3), 1927–1938. https://doi.org/10.1007/s12035-016-9781-x
21. Izadi, M. S., Radahmadi, M., Ghasemi, M., & Rayatpour, A. (2018). Effects of isolation and social subchronic stresses on food intake and levels of leptin, ghrelin, and glucose in male rats. Advanced Biomedical Research, 7, 118. https://doi.org/10.4103/abr.abr_28_18
22. Jiang, H., Long, X., Wang, Y., Zhang, X., Chen, L., Yang, X., Zhao, B., Zhang, Y., Chai, Y., & Bao, T. (2024). Acupuncture ameliorates depression-like behaviors through modulating the neuroinflammation mediated by tlr4 signaling pathway in rats exposed to chronic restraint stress. Molecular Neurobiology, 61(5), 2606–2619. https://doi.org/10.1007/s12035-023-03737-6
23. Kamaei, A. K., Hosseini, S. F., Teimourparsaei, P., Payamani, M., & Vaseghi, S. (2024). The effect of acute crocin on behavioral changes and BDNF expression level in socially isolated rats. Naunyn-Schmiedeberg's Archives of Pharmacology, 397(6), 3929–3944. https://doi.org/10.1007/s00210-023-02843-5
24. Kim, M., Netser, S., Wagner, S., & Harony-Nicolas, H. (2025). Juvenile social isolation in Sprague Dawley rats does not have a lasting impact on social behavior in adulthood. Scientific Reports, 15(1), 12981. https://doi.org/10.1038/s41598-025-95920-z
25. Leonard B. E. (2018). Inflammation and depression: a causal or coincidental link to the pathophysiology?. Acta Neuropsychiatrica, 30(1), 1–16. https://doi.org/10.1017/neu.2016.69
26. Liu, F., Jia, Y., Zhao, L., Xiao, L. N., Cheng, X., Xiao, Y., Zhang, Y., Zhang, Y., Yu, H., Deng, Q. E., Zhang, Y., Feng, Y., Wang, J., Gao, Y., Zhang, X., & Geng, Y. (2024). Escin ameliorates CUMS-induced depressive-like behavior via BDNF/TrkB/CREB and TLR4/MyD88/NF-κB signaling pathways in rats. European Journal of Pharmacology, 984, 177063. https://doi.org/10.1016/j.ejphar.2024.177063
27. Murínová, J., Hlaváčová, N., Chmelová, M., Riečanský. (2017). The evidence for altered BDNF expression in the brain of rats reared or housed in social isolation: a systematic review. Frontiers in Behavioral Neuroscience, 1, 101. https://doi.org/10.3389/fnbeh.2017.00101
28. Nie, X., Kitaoka, S., Tanaka, K., Segi-Nishida, E., Imoto, Y., Ogawa, A., Nakano, F., Tomohiro, A., Nakayama, K., Taniguchi, M., Mimori-Kiyosue, Y., Kakizuka, A., Narumiya, S., & Furuyashiki, T. (2018). The innate immune receptors TLR2/4 mediate repeated social defeat stress-induced social avoidance through prefrontal microglial activation. Neuron, 99(3), 464– 479.e7. https://doi.org/10.1016/j.neuron.2018.06.035
29. Pitcairn, S.R., Ortelli, O.A., Weiner, J.L. (2024). Effects of early social isolation and adolescent single prolonged stress on anxiety-like behaviors and voluntary ethanol consumption in female Long Evans rats. Alcohol, Clinical & Experimental Research, 48(8), 1586–1599. https://doi.org/10.1111/acer.15397
30. Shirayama, Y., Iwata, M., Fujita, Y., Oda, Y., & Hashimoto, K. (2022). The Toll-like receptor 4 antagonist TAK-242 induces antidepressant-like effects in a rat learned helplessness model of depression through BDNF-TrkB signaling and AMPA receptor activation. Behavioural Brain Research, 423, 113769. https://doi.org/10.1016/j.bbr.2022.113769
31. Todorović, N., & Filipović, D. (2017). Prefrontal cortical glutathione-dependent defense and proinflammatory mediators in chronically isolated rats: Modulation by fluoxetine or clozapine. Neuroscience, 355, 49–60. https://doi.org/10.1016/j.neuroscience.2017.04.044
32. Toth, M., Mikics, E., Tulogdi, A., Aliczki, M., & Haller, J. (2011). Post-weaning social isolation induces abnormal forms of aggression in conjunction with increased glucocorticoid and autonomic stress responses. Hormones and Behavior, 60(1), 28–36. https://doi.org/10.1016/j.yhbeh.2011.02.003
33. Turan, İ., & Sayan Özaçmak, H. (2025). Sosyal izolasyonun neden olduğu stresin oksidatif stres belirteçleri ve öğrenme ile ilişkili nörogranin/CAMKII/CREB proteinlerine etkisi. Kocatepe Tıp Dergisi, 26(2), 148-155. https://doi.org/10.18229/kocatepetip.1540581
34. Weber, M. D., Frank, M. G., Sobesky, J. L., Watkins, L. R., & Maier, S. F. (2013). Blocking toll-like receptor 2 and 4 signaling during a stressor prevents stress-induced priming of neuroinflammatory responses to a subsequent immune challenge. Brain, Behavior, and Immunity, 32, 112–121. https://doi.org/10.1016/j.bbi.2013.03.004
35. Xiao, Z., Cao, Z., Yang, J., Jia, Z., Du, Y., Sun, G., Lu, Y., & Pei, L. (2021). Baicalin promotes hippocampal neurogenesis via the Wnt/β-catenin pathway in a chronic unpredictable mild stress-induced mouse model of depression. Biochemical Pharmacology, 190, 114594. https://doi.org/10.1016/j.bcp.2021.114594
36. Zhang, K., Lin, W., Zhang, J., Zhao, Y., Wang, X., & Zhao, M. (2020). Effect of Toll-like receptor 4 on depressive-like behaviors induced by chronic social defeat stress. Brain and Behavior, 10(3), e01525. https://doi.org/10.1002/brb3.1525